US2002123485A1PendingUtilityA1

Epoxy steroidal aldosterone antagonist and beta-adrenergic antagonist combination therapy for treatment of congestive heart failure

55
Priority: Jul 27, 2000Filed: Jul 27, 2001Published: Sep 5, 2002
Est. expiryJul 27, 2020(expired)· nominal 20-yr term from priority
Inventors:John AlexanderJoseph Schuh
A61K 31/58A61P 43/00A61P 9/00A61K 45/06A61P 9/12
55
PatentIndex Score
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Claims

Abstract

A combination therapy comprising a therapeutically-effective amount of an epoxy-steroidal aldosterone receptor antagonist and a therapeutically-effective amount of a beta-adrenergic antagonist is described for treatment of circulatory disorders, including cardiovascular disorders such as hypertension, congestive heart failure, cirrhosis and ascites. Preferred beta-adrenergic antagonists are those compounds having high potency and bioavailability. Preferred epoxy-steroidal aldosterone receptor antagonists are 20-spiroxane steroidal compounds characterized by the presence of a 9α,11α-substituted epoxy moiety. A preferred combination therapy includes the beta-adrenergic antagonist metoprolol ((±)1-(isopropylamino)-3-[p-(2-methoxyethyl)phenoxyl]-2-propanolol succinate) and the aldosterone receptor antagonist epoxymexrenone.

Claims

exact text as granted — not AI-modified
What is claimed is:  
     
         1 . A combination comprising a first amount of an aldosterone receptor antagonist and a second amount of a beta-adrenergic antagonist, wherein said aldosterone receptor antagonist and beta-adrenergic antagonist together comprise a therapeutically-effective amount of said aldosterone receptor antagonist and said beta-adrenergic antagonist.  
     
     
         2 . The combination of  claim 1  wherein said aldosterone receptor antagonist is selected from epoxy-containing compounds.  
     
     
         3 . The combination of  claim 2  wherein said epoxy-containing compound has an epoxy moiety fused to the “C” ring of the steroidal nucleus of a 20-spiroxane compound.  
     
     
         4 . The combination of  claim 3  wherein said 20-spiroxane compound is characterized by the presence of a 9a-,11a-substituted epoxy moiety.  
     
     
         5 . The combination of  claim 2  wherein said epoxy-containing compound is selected from the group consisting of: 
 pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo, g-lactone, methyl ester, (7a,11a,17a)-;  
 pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-dimethyl ester,(7a,11a,17a)-;  
 3′H-cyclopropa[6,7] pregna-4,6-diene-21-carboxylic acid, 9,11-epoxy-6,7-dihydro-17-hydroxy-3-oxo-, g-lactone, (6b,7b,11b,17b)-;  
 pregn-4-ene-7,21-dicarboxylic acid,9,11-epoxy-17-hydroxy-3-oxo-,7-(1-methylethyl) ester, monopotassium salt,(7a,11a,17a)-;  
 pregn-4-ene-7,21-dicarboxylic acid,9,11,-epoxy-17-hydroxy-3-oxo-,7-methyl ester, monopotassium salt, (7a,11a,17a)-;  
 3′H-cyclopropa[6,7]pregna-1,4,6-triene-21-carboxylic acid, 9,11-epoxy-6,7-dihydro-17-hydroxy-3-oxo-, g-lactone(6a,7a,11.a)-;  
 3′H-cyclopropa[6,7]pregna-4,6-diene-21-carboxylic acid, 9,11-epoxy-6,7-dihydro-17-hydroxy-3-oxo-, methyl ester, (6a,7a,11a,17a)-;  
 3′H-cyclopropa [6, 7]pregna-4,6-diene-21-carboxylic acid, 9,11-epoxy-6,7-dihydro-17-hydroxy-3-oxo-, monopotassium salt, (6a,7a,11a,17a) -;  
 3′H-cyclopropa[6,7]pregna-4,6-diene-21-carboxylic acid, 9,11-epoxy-6,7-dihydro-17-hydroxy-3-oxo-, g-lactone, (6a,7a,11a.,17a)-;  
 pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-, g-lactone, ethyl ester, (7a,11a,17a)-; and  
 pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-, g-lactone, 1-methylethyl ester, (7a,11a,17a)-.  
 
     
     
         6 . The combination of  claim 4  wherein said epoxy-steroidal-type compound is eplerenone.  
     
     
         7 . The combination of  claim 6  wherein said beta-adrenergic antagonist is selected from the group consisting of acebutolol, alprenolol, amosulalol, arotinolol, atenolol, befunolol, bevantolol, bisoprolol, bopindolol, bucumolol, bucindolol, bunitrolol, butofilolol, carteolol, carvedilol, celiprolol, cloranolol, indenolol, labetalol, levoprolol, mepindolol, metipranolol, metoprolol, nadolol, nebivolol, nifenalol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, timolol, toprol, and viskenit.  
     
     
         8 . The combination of  claim 6  wherein said beta-adrenergic antagonist is selected from the group consisting of Acc 9369, AMO-140, betaxolol, capsinolol, carazolol, CP-331684, diprafenone, ersentilide, esmolol, esprolol, Fr-172516, ISV-208, L-653328, laniolol, levobunolol, LM-2616, nipradilol, Pharmaprojects No 5279, S-atenolol, SB-226552, SR-58894A, SR-59230A. talinolol, tertatolol, tilisolol, TZC-5665, UK-1745, xamoterol, and YM-430.  
     
     
         9 . The combination of  claim 7  further characterized by said beta-adrenergic antagonist and said epoxy-steroidal aldosterone receptor antagonist being present in said combination in a weight ratio range from about one-to-one to about one-to-twenty of said beta-adrenergic antagonist to said aldosterone receptor antagonist.  
     
     
         10 . The combination of  claim 9  wherein said weight ratio range is from about one-to-five to about one-to-fifteen.  
     
     
         11 . The combination of  claim 10  wherein said weight ratio range is about one-to-ten.  
     
     
         12 . The combination of  claim 6  wherein the beta-adrenergic antagonist comprises carvedilol or a pharmaceutically-acceptable salt thereof.  
     
     
         13 . The combination of  claim 6  wherein the beta-adrenergic antagonist comprises metoprolol or a pharmaceutically-acceptable salt thereof.  
     
     
         14 . The combination of  claim 6  wherein the beta-adrenergic antagonist comprises bisoprolol or a pharmaceutically-acceptable salt thereof.  
     
     
         15 . The combination of  claim 6  wherein the beta-adrenergic antagonist comprises bucindolol or a pharmaceutically-acceptable salt thereof.  
     
     
         16 . The combination of  claim 6  wherein the beta-adrenergic antagonist comprises propranolol or a pharmaceutically-acceptable salt thereof.  
     
     
         17 . The combination of  claim 6  wherein the beta-adrenergic antagonist comprises esmolol or a pharmaceutically-acceptable salt thereof.  
     
     
         18 . The combination of  claim 6  wherein the beta-adrenergic antagonist comprises acebutolol or a pharmaceutically-acceptable salt thereof.  
     
     
         19 . The combination of  claim 6  wherein the beta-adrenergic antagonist comprises sotalol or a pharmaceutically-acceptable salt thereof.  
     
     
         20 . The combination of  claim 6  wherein the beta-adrenergic antagonist comprises labetalol or a pharmaceutically-acceptable salt thereof.  
     
     
         21 . The combination of  claim 1  wherein said aldosterone antagonist is spironolactone.  
     
     
         22 . The combination of  claim 21  wherein said beta-adrenergic antagonist is selected from the group consisting of acebutolol, alprenolol, amosulalol, arotinolol, atenolol, befunolol, bevantolol, bisoprolol, bopindolol, bucumolol, bucindolol, bunitrolol, butofilolol, carteolol, carvedilol, celiprolol, cloranolol, indenolol, labetalol, levoprolol, mepindolol, metipranolol, metoprolol, nadolol, nebivolol, nifenalol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, timolol, toprol, and viskenit.  
     
     
         23 . The combination of  claim 21  wherein said beta-adrenergic antagonist is selected from the group consisting of Acc 9369, AMO-140, betaxolol, capsinolol, carazolol, CP-331684, diprafenone, ersentilide, esmolol, esprolol, Fr-172516, ISV-208, L-653328, laniolol, levobunolol, LM-2616, nipradilol, Pharmaprojects No 5279, S-atenolol, SB-226552, SR-58894A, SR-59230A. talinolol, tertatolol, tilisolol, TZC-5665, UK-1745, xamoterol, and YM-430.  
     
     
         24 . The combination of  claim 22  further characterized by said beta-adrenergic antagonist and said aldosterone receptor antagonist being present in said combination in a weight ratio range from about one-to-one to about one-to-twenty of said beta-adrenergic antagonist to said aldosterone receptor antagonist.  
     
     
         25 . The combination of  claim 24  wherein said weight ratio range is from about one-to-five to about one-to-fifteen.  
     
     
         26 . The combination of  claim 25  wherein said weight ratio range is about one-to-ten.  
     
     
         27 . The combination of  claim 21  wherein the beta-adrenergic antagonist comprises carvedilol or a pharmaceutically-acceptable salt thereof.  
     
     
         28 . The combination of  claim 21  wherein the beta-adrenergic antagonist comprises metropolol or a pharmaceutically-acceptable salt thereof.  
     
     
         29 . The combination of  claim 21  wherein the beta-adrenergic antagonist comprises bisoprolol or a pharmaceutically-acceptable salt thereof.  
     
     
         30 . The combination of  claim 21  wherein the beta-adrenergic antagonist comprises bucindolol or a pharmaceutically-acceptable salt thereof.  
     
     
         31 . The combination of  claim 21  wherein the beta-adrenergic antagonist comprises propranolol or a pharmaceutically-acceptable salt thereof.  
     
     
         32 . The combination of  claim 21  wherein the beta-adrenergic antagonist comprises esmolol or a pharmaceutically-acceptable salt thereof.  
     
     
         33 . The combination of  claim 21  wherein the beta-adrenergic antagonist comprises acebutolol or a pharmaceutically-acceptable salt thereof.  
     
     
         34 . The combination of  claim 21  wherein the beta-adrenergic antagonist comprises sotalol or a pharmaceutically-acceptable salt thereof.  
     
     
         35 . The combination of  claim 21  wherein the beta-adrenergic antagonist comprises labetalol or a pharmaceutically-acceptable salt thereof.  
     
     
         36 . The combination of  claim 1  wherein said beta-adrenergic antagonist is selected from the group consisting of acebutolol, alprenolol, amosulalol, arotinolol, atenolol, befunolol, bevantolol, bisoprolol, bopindolol, bucumolol, bucindolol, bunitrolol, butofilolol, carteolol, carvedilol, celiprolol, cloranolol, indenolol, labetalol, levoprolol, mepindolol, metipranolol, metoprolol, nadolol, nebivolol, nifenalol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, timolol, toprol, and viskenit.  
     
     
         37 . The combination of  claim 1  wherein said beta-adrenergic antagonist is selected from the group consisting of Acc 9369, AMO-140, betaxolol, capsinolol, carazolol, CP-331684, diprafenone, ersentilide, esmolol, esprolol, Fr-172516, ISV-208, L-653328, laniolol, levobunolol, LM-2616, nipradilol, Pharmaprojects No 5279, S-atenolol, SB-226552, SR-58894A, SR-59230A. talinolol, tertatolol, tilisolol, TZC-5665, UK-1745, xamoterol, and YM-430.  
     
     
         38 . The combination of  claim 36  wherein said aldosterone receptor antagonist is eplerenone.  
     
     
         39 . The combination of  claim 37  wherein said aldosterone receptor antagonist is eplerenone.  
     
     
         40 . The combination of  claim 36  wherein said aldosterone receptor antagonist is spironolactone.  
     
     
         41 . The combination of  claim 37  wherein said aldosterone receptor antagonist is spironolactone.  
     
     
         42 . A pharmaceutical composition comprising a first amount of an aldosterone receptor antagonist and a second amount of a beta-adrenergic antagonist, wherein said aldosterone receptor antagonist and beta-adrenergic antagonist together comprise a therapeutically-effective amount of said aldosterone receptor antagonist and said beta-adrenergic antagonist.  
     
     
         43 . The pharmaceutical composition of  claim 42  wherein said aldosterone receptor antagonist is selected from epoxy-containing compounds.  
     
     
         44 . The pharmaceutical composition of  claim 43  wherein said epoxy-containing compound has an epoxy moiety fused to the “C” ring of the steroidal nucleus of a 20-spiroxane compound.  
     
     
         45 . The pharmaceutical composition of  claim 44  wherein said 20-spiroxane compound is characterized by the presence of a 9a-,11a-substituted epoxy moiety.  
     
     
         46 . The pharmaceutical composition of  claim 45  wherein said epoxy-steroidal-type compound is eplerenone.  
     
     
         47 . The pharmaceutical composition of  claim 42  wherein said aldosterone receptor antagonist is spironolactone.  
     
     
         48 . A therapeutic method for treating a cardiovascular disorder, said method comprising administering to a subject susceptible to or afflicted with such disorder a first amount of an aldosterone receptor antagonist and a second amount of a beta-adrenergic antagonist, wherein said aldosterone receptor antagonist and beta-adrenergic antagonist together comprise a therapeutically-effective amount of said aldosterone receptor antagonist and said beta-adrenergic antagonist.  
     
     
         49 . The method of  claim 48 , wherein said cardiovascular disorder is selected from the group consisting of hypertension, congestive heart failure, cirrhosis and ascites.  
     
     
         50 . The method of  claim 49 , wherein said cardiovascular disorder is hypertension.  
     
     
         51 . The method of  claim 49 , wherein said cardiovascular disorder is congestive heart failure.

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